Ferritin, the main intracellular iron storage protein in both prokaryotes and eukaryotes, is a large (nearly 480 kDa) multi-subunit complex comprising 24 polypeptide subunits. This iron storage complex, found in high concentrations in serum, is capable of containing as many as 4,500 atoms of iron ions (Fe3+) within a hydrous ferric oxide core. In mammals, there are two distinct subunit classes, heavy (H) and light (L) type with a molecular weight of about 21 kDa and 19 kDa, respectively, which share about 54% sequence identity. The H and L subunits appear to have different functions: the L subunit enhances the stability of the iron core while the H subunit has a ferroxidase activity that appears to be necessary for the rapid uptake of ferrous iron. H rich ferritins are localized in tissues undergoing rapid changes in local ion concentration. For instance, expression of the H subunit is preferentially increased relative to the L subunit in cells undergoing differentiation, development, proliferation and metabolic stress.
The brain imposes heightened challenges to iron acquisition because of the highly developed tight junctions that bind neighboring endothelial cells that make up the brain microvasculature. These junctions prevent the paracellular flux of molecules into the brain. The resulting blood-brain barrier (BBB) is a highly effective mechanism for protecting the brain from potentially harmful substances that circulate in the blood. A consequence of such a blockade, however, is that specific transport mechanisms must be designed for the many trophic substances that are required for normal brain function. Pinocytosis is a potential method to circumvent the BBB, but vesicles that arise from pinocytosis contribute relatively little to nonspecific transport of compounds across the brain vascular endothelial cells.
Traditionally, transferrin has been considered the primary mechanism for cellular iron delivery, and a transferrin mediated transport system has been identified in the BBB (Jefferies W. A., et al. Nature 312: 162-163, 1984; Fishman J., Rubin J., Handrahan J., Connor J., Fine R. J. Neurosci. Res. 18: 299-304, 1987). However, transferrin-independent iron delivery to the brain has been suggested using hypotransferrinemic mice (Malecki E. A., Cook B. M., Devenyi A. G., Beard J. L. and Connor J. R. J. Neurol. Sci. 170: 112-118, 1999). It has been proposed that lactoferrin may also transport iron into the brain (Ji B., et al. Life Sci. 78: 851-855, 2005), but lactoferrin concentrations in serum are barely detectable and this protein is generally found within cells (neutrophils) and is thus unlikely to contribute to iron transport to the brain or other organs.